Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial.
Level 2 - randomized trial
Individual randomized, double-blind, placebo-controlled trial
PubMed 41174221 · doi:10.1038/s43587-025-00996-x
What was done
Fifty healthy middle-aged adults were randomized in a double-blind, placebo-controlled trial to receive either oral urolithin A (1,000 mg daily) or placebo for 4 weeks. Primary outcomes measured at baseline and day 28 were phenotypic shifts in peripheral CD3+ T cell subsets and immune metabolic remodeling. Secondary and exploratory outcomes included plasma cytokine levels (IL-6, TNF, IL-1β, IL-10), immune cell populations assessed by flow cytometry, immune cell functional capacity, mitochondrial biogenesis, and single-cell RNA sequencing.
What was found
Compared with placebo, urolithin A significantly increased peripheral naive-like, less terminally exhausted CD8+ T cells (treatment difference: 0.50 percentage points; 95% CI: 0.16 to 0.83; P = 0.0437) and enhanced CD8+ fatty acid oxidation capacity (treatment difference: 14.72 percentage points; 95% CI: 6.46 to 22.99; P = 0.0061). Urolithin A also augmented CD8+ mitochondrial biogenesis, increased peripheral CD56dim CD16bright NK cells and nonclassical CD14lo CD16hi monocytes, and improved activation-induced T cell TNF secretion and monocyte bacterial uptake. Exact numeric values for cytokine levels and secondary cell counts were not reported in the abstract.
Why it matters
This trial provides randomized human proof-of-concept that pharmacological induction of mitophagy via urolithin A can remodel immune cell subsets and metabolism, supporting further exploration of mitophagy-directed strategies to mitigate immunosenescence.
Limits
The study is limited by a small sample size (n = 50), short follow-up duration (4 weeks), and reliance on cellular surrogate markers rather than hard clinical outcomes such as infection rates or vaccine responses. The absolute change in naive-like CD8+ cells was modest (0.50 percentage points).
Cited by
- supports 1,000 mg per day of urolithin A in older adults increases CD8-positive T cells and natural killer cells while reducing markers of cellular senescence.